For the first time in nearly 30 years, a gene has been identified that is linked to the development of a hereditary form of Alzheimer’s disease. Three genes had already been identified, and researchers from the VUmc, Erasmus MC and TU Delft have now discovered a fourth: the SORL1 gene. It is vitally important to patients and their families to find out whether their Alzheimer’s has hereditary origins. More detailed information on hereditariness also results in fresh insights regarding the processes involved with Alzheimer’s disease.
Familial Alzheimer’s is a rare form of the disease in which the condition is passed from parent to child and results in dementia at a young age. In the 1990s, it became clear that an abnormality in one of three genes (PSEN1, PSEN2 and APP) can explain the clinical picture in some of the affected families. Earlier scientific publications demonstrated that genetic abnormalities in the SORL1 gene increase the risk of Alzheimer’s disease. However, it remained unclear which abnormalities in the SORL1 gene were dangerous and which were benign.
Different patient test group
In contrast to the research conducted into the first three genes, the researchers did not look for abnormalities in the SORL1 gene within families with an incidence of hereditary Alzheimer’s, but within a large group of 2,000 anonymous Dutch Alzheimer’s patients and healthy test subjects. Dr Henne Holstege, Principle Researcher at the VUmc: ‘After sorting the SORL1 abnormalities based on their characteristics, we established that some abnormalities in the SORL1 gene almost certainly result in dementia. Others result in a more than tenfold increase in the risk of dementia, while others proved to be benign’. The researchers successfully confirmed these findings with a second, independent group of 3,000 people, once again comprising anonymous Alzheimer’s patients and healthy test subjects. The results make it clear that the SORL1 gene now really must be added as the fourth causal Alzheimer gene.
Bioinformatics, the application of informatics expertise to biological data, made a significant contribution to this discovery. Prof. Marcel Reinders from the TU Delft Bioinformatics Lab worked closely with the VUmc to research the connection between the genes and the clinical picture. The researchers recently jointly published their findings in the ‘European Journal of Human Genetics’ a scientific journal.
The discovery of this gene means that, in the future, it will be possible to establish the cause of the disease in a greater number of Alzheimer’s patients. There are still many families with a relatively high incidence of Alzheimer’s whereby no mutation in the known three causal genes can be found. In these cases, a SORL1 mutation could potentially be present. If so, family members will have the opportunity to seek advice and make any necessary decisions regarding their future.
Accumulation of Alzheimer proteins
Determining abnormalities in the SORL1 gene that cause Alzheimer’s is also important for further research into the development of the disease. As is the case with the previously discovered genes, SORL1 is linked to preventing accumulations of Alzheimer proteins in the brain: amyloid plaques.